1. Field of the Invention
Methods for treating and preventing acute respiratory distress syndrome.
2. Description of the Related Art
Adult Respiratory Distress Syndrome (ARDS) is a descriptive expression which is applied to a large number of acute, diffusely infiltrative pulmonary lesions of different etiology if they are associated with a severe gas exchange disorder (in particular arterial hypoxemia). The acute respiratory distress syndrome (ARDS; also known as the adult respiratory distress syndrome) is an inflammatory disorder characterized by the accumulation of neutrophils in the lung and the development of non-cardiogenic pulmonary edema [Repine, Lancet (1992); 339: 466-469]. ARDS is part of a spectrum of acute lung inflammatory diseases involving adults and neonates. In neonates, the disease is often called hyaline membrane disease. Once established, ARDS has an approximately 50% mortality, largely because there are still no specific treatments for the syndrome. Patients with major trauma, sepsis or other specific disorders are at risk for ARDS.
Acute respiratory distress syndrome (ARDS) is characterized by the development of sudden breathlessness within hours to days of an inciting event. ARDS typically develops within 12-48 hours after the inciting event, although, in rare instances, it may take up to a few days. Persons developing ARDS are critically ill, often with multisystem organ failure. It is a life-threatening condition; therefore, hospitalization is required for prompt management.
ARDS is associated with severe and diffuse injury to the alveolar-capillary membrane (the air sacs and small blood vessels) of the lungs. Fluid accumulates in some alveoli of the lungs, while some other alveoli collapse. This alveolar damage impedes the exchange of oxygen and carbon dioxide, which leads to a reduced concentration of oxygen in the blood. Low levels of oxygen in the blood cause damage to other vital organs of the body such as the kidneys.
ARDS occurs in children as well as adults. The estimated annual frequency of ARDS is reported as 75 cases per 100,000 people. Mortality (death) rates have been reported to be in the range of 30-40%.
A number of risk factors are associated with the development of ARDS, including sepsis (presence of various pathogenic microorganisms, or their toxins, in the blood or tissues), severe traumatic injury (especially multiple fractures), severe head injury, injury to the chest, aspiration, diffuse pulmonary infection, near-drowning, fracture of the long bones, acute pancreatitis, drug overdose, aspiration, viral pneumonias, bacterial and fungal pneumonias, near drowning, toxic inhalations, transfusion, and cardiopulmonary bypass surgery. Among these causes, sepsis has a particularly high incidence and poor prognosis for acute lung injury (Montgomery, A. B. et al., Am. Rev. Respir. Dis. (1985) 132, 485-489, Knaus, W. A. et al., Am. J. Respir. Crit. Care Med. (1994) 150, 311-317; and Bernard, G. R. et al., Am. J. Respir. Crit. Care Med. (1994) 149, 818-824). The definition of sepsis syndrome specifies that it does not necessarily require clinical findings as an infection (Bone, R. C. et al., Chest (1992) 101, 1644-1655: Crit. Care Med. (1992) 20, 864-874). Sepsis as used herein collectively refers to both sepsis and sepsis syndrome.
Persons with ARDS are hospitalized and require treatment in an intensive care unit. Treatment is primarily supportive using a mechanical respirator and supplemental oxygen. Intravenous fluids are given to provide nutrition and prevent dehydration, and are carefully monitored to prevent fluid from accumulating in the lungs (pulmonary edema). Because infection is often the underlying cause of ARDS, appropriate antibiotic therapy is administered. Corticosteroids may sometimes be administered in late phases of ARDS to reduce inflammation or if the patient is in shock. Diuretics to eliminate fluid from the lungs are also used Inhaled drugs administered by respiratory therapists are often administered to decrease inflammation and provide respiratory comfort. While there is a 60-70% survival rate, many survivors of ARDS have residual lung impairment. Typically, the lung dysfunction is mild, but ARDS can lead to severe lung damage and a reduced health-related quality of life.
As was mentioned above, the therapy of ARDS consists mainly in the earliest possible application of different forms of ventilation to raise the oxygen concentration of the respiratory air. However, ventilation with pressure and high FiO2 (Fraction of Inspired Oxygen; proportion of oxygen in the respiratory air), can damage the lungs therefore necessitating even higher pressures and higher FiO2 in order to obtain an adequate oxygenation of the blood.
Pathological conditions associated with ARDS include pulmonary edema due to increased permeability based on injuries in the pulmonary microvascular endothelia (Matthay, M. A., Clin. Chest Med. (1990) 11, 575-580). A variety of pharmacological agents including pulmonary vasodilators, anti-inflammatory agents, anti-oxidants, inhibitors of thromboxane synthetase, exogenous surfactants, inhaled vasodilators (nitric oxide), anti-endotoxin and anti-cytokine agents (Kollef et al., supra and Ware et al et al., supra) have been tried without success. Therefore there is a need for new therapies to prevent or treat ARDS or other forms of acute lung injury (ALI).